Project Summary Individuals with stimulant use disorder show a high prevalence of sleep problems, and sleep disruption may affect the course of drug addiction. Given this bidirectional interaction, understanding the neurobiological mech- anisms linking sleep impairment and stimulant abuse may provide key information for developing broadly effec- tive treatments. My previous studies have shown that methamphetamine impairs actigraphy-based sleep in rhe- sus monkeys and that presentation of methamphetamine-associated cues in a monkey reinstatement model of relapse resulted in sleep impairment. Recent research has implicated the orexin (hypocretin) system as a critical regulator of reinforcing processes as well as sleep-wake states, and an interplay between orexin-1 (OX1) and orexin-2 (OX2) receptors may regulate the relationship between sleep and stimulant abuse. The working hy- pothesis of this application is that orexin-mediated mechanisms play a major role in the interplay be- tween methamphetamine taking, methamphetamine-associated triggers of relapse, and sleep impair- ment. My Research Strategy is organized around three Specific Aims to be conducted in female and male rhesus monkeys. Aim 1 (K99 Phase) will evaluate the hypothesis that experimenter-administered daytime metham- phetamine will disrupt nighttime sleep by decreasing time spent in slow-wave (N3) sleep and rapid eye move- ment (REM) sleep, and that OX2 receptors modulate methamphetamine-induced sleep impairment. I will inves- tigate the effects of subtype selective orexin receptor antagonists on sleep-wake cycles using polysomnography based on telemetric recording of electroencephalography/electromyography/electrooculography (EEG/EMG/EOG) and quantitative behavioral observations. Aim 2 (R00 Phase) will evaluate the hypothesis that OX1 receptors modulate the reinforcing effects of methamphetamine, whereas OX2 receptors mediate sleep impairment in the context of methamphetamine self-administration. I will investigate the effects of subtype-se- lective orexin receptor antagonists on i.v. methamphetamine self-administration, and sleep will be evaluated using actigraphy. Aim 3 (R00 Phase) will evaluate the hypothesis that OX1 receptors are associated with the relapse-like effects of methamphetamine, whereas both OX1 and OX2 receptors are involved in reinstatement- induced sleep impairment. I will conduct reinstatement studies in animals implanted with EEG/EMG/EOG telem- etry. I will investigate the effects of OX1 or OX2 antagonists on methamphetamine- and/or cue-induced rein- statement, as well as on drug- and/or cue-induced sleep impairment, in monkeys self-administering metham- phetamine. For all studies, quantitative pharmacology will be used to assess potential OX1 and OX2 receptor interactions in mediating the effects of methamphetamine. Overall, the lack of treatments for stimulant use dis- order and stimulant-induced sleep impairment represents a significant unmet public health need in the U.S. and worldwide. These results may inform the potential of orexin receptor antagonists as prospective targets for the understanding and treatment of stimulant abuse and stimulant-induced sleep impairment.